This application claims priority to U.S. Provisional Patent Application, Ser. No. 60/557,069, entitled “NOVEL SEROTONIN REUPTAKE INHIBITORS” filed on Mar. 26, 2004, having Maria G. Miranda, Kevin G. Pinney, and James N. Dorsey, listed as the inventors, the entire content of which is hereby incorporated by reference.
This invention pertains to novel serotonin reuptake inhibitors which comprise a structural homologue of a serotonin reuptake inhibitor, known to treat depression, and a piperazine moiety, known to treat sexual dysfunction induced by serotonin-selective reuptake inhibitors (SSRIs).
Depression is a common, life-disrupting, potentially lethal illness that can affect both sexes and all ages. Untreated major depression remains a serious public health problem ands its incidences are staggering. Its peak onset is in the early adult years. Suicide occurs in as many as 15% of patients with depression, especially those with recurrent episodes and hospitalizations. Therefore it becomes evident that treatment of depression is a matter of prime importance. Depression has no single cause; often, it results from a combination of factors. Whatever its cause, depression is not just a state of mind. It is related to physical changes in the brain, and connected to an imbalance of a type of chemical that carries signals in the brain and nerves. These chemicals are called neurotransmitters. Among the most important neurotransmitters related with depression are serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Serotonin plays a very important role in the mood disorders, especially in anxiety and depression, aggression and impulsivity. Regulation of the mood disorders is possible either by agonistic or antagonistic action on a certain type of the serotonin receptors.
Serotonin-selective reuptake inhibitors (SSRIs), such as fluoxetine (PROZAC®), have traditionally been the mainstay of treatment for clinical depression—replacing the more toxic tricyclic antidepressants (TCAs). SSRIs have a more favorable adverse reaction profile in comparison to the TCAs and are much easier to tolerate. SSRIs exert their therapeutic effect by blocking the reuptake of serotonin into the presynaptic nerve terminal, thus increasing the synaptic concentration of serotonin. It is also believed that SSRIs increase the efficacy of the serotonin (5-HT) neurons by desensitizing 5-HT autoreceptors located on the presynaptic 5-HT nerve terminals. The ability of the 5-HT autoreceptors to inhibit the release of 5-HT decreases after long-term treatment with SSRIs, with the net effect being that a greater amount of 5-HT is released per impulse. The release of 5-HT from these Neurons, thus, becomes more efficient.
Unfortunately, SSRIs are not innocuous drugs. In spite of the progress in the treatment of depression with the advent of the SSRIs, some troublesome side effects still remain—most notably, sexual dysfunction. As prescribing of SSRIs increased, the side effect of sexual dysfunction emerged, and clinicians searched for methods to treat or reverse SSRI-induced sexual dysfunction. A number of pharmacological agents—notably, drugs in the piperazine class—have been used to reverse SSRI-induced sexual dysfunction.
It is widely believed that a number of monoamine neurotransmitters have a role in the etiology of depression and, consequently, its treatment. The most notable of these neurotransmitters include norepinephrine (NE) and serotonin (5-HT). It is well known that inhibiting the reuptake of NE or 5-HT (or both) has elicited a favorable response in patients being treated for depression. Without question, however, inhibition of 5-HT reuptake has been the most widely studied, and treatment of depression has focused on inhibiting the reuptake mechanism of the neurotransmitter. Indeed, it was this premise which led to the hypothesis that altering 5-HT function could lead to an effective mechanism in the treatment of depression.
Research in the treatment of depression remains focused on 5-HT because a good number of selective 5-HT reuptake blockers tested in clinical trials have been effective in treating major depression. The general mechanism of action is hypothesized as enhanced 5-HT neurotransmission due to the increased availability of 5-HT in the synapse of these neurons (Blier et al., 1990). SSRIs generally have a 50- to 100-fold or greater selectivity for the inhibition of serotonin uptake in vitro when compared to their ability to inhibit NE or DA uptake (Lemberger et al., 1985).
Sexual dysfunction is a common problem in affective disorders such as major depression. It is important to note, however, that the drugs used in the treatment of depression can cause sexual dysfunction as well. Antidepressants such as the TCAs, monoamine oxidase inhibitors, and the SSRIs have all been reported to cause sexual side effects. The inhibitory effects of the SSRIs on sexual function are well documented, and the frequency of occurrence varies widely. By switching to a less serotonergic drug, it is surmised that the non-selective effects of 5-HT can be reduced within the synapse of the 5-HT neuron. Although the connection between serotonergic activity and sexual function is not straightforward, it is believed that the increased central serotonergic activity of SSRIs (at the receptor subtypes 5-HT1A, 5-HT1B, 5-HT2C, 5-HT2A and 5-HT3) plays a role in the emergence of sexual dysfunction (Modell et al., 1997). It follows, therefore, that reducing the activity of SSRIs at these receptors could allow the suppression or inhibition of the sexual response to be corrected. Strategies which have been tried in treating or reversing sexual dysfunction include: titration of an antidepressant dose, scheduling of a drug holiday during treatment, and administering a second drug (along with an SSRI, for example) to counteract the SSRI's sexual side effects.
The drugs which have been administered along with an SSRI include a broad range of medicinal agents. Drugs such as: amantadine (normally used in the treatment of Parkinsonism), cyproheptadine, buspirone, trazodone, nefazodone, methylphenidate, mianserin, yohimbine, and even sildenafil citrate have been used. Bupropion has also been of benefit. The success of each of these agents varies widely, but the best studied agents include bupropion and buspirone (Hyttel, 1982). Buspirone, which has a pyrimidinyl-piperazine group, is generally used in the treatment of generalized anxiety disorder and has been used with some success in treating patients with SSRI-induced sexual dysfunction (Gonzalez-Heydrich, 1990) It is interesting to note that other piperazine-containing groups (specifically, functionalized phenylpiperazines) have likewise been used with success in treating sexual dysfunction. These agents include: sildenafil citrate, trazodone, and nefazodone.
What is needed, therefore, is an SSRI with an adverse reaction profile that is devoid of sexual side effects.